DESCRIPTION (Verbatim from the application): The aim of this proposal is to assess the contribution of the mitochondrial genome to hypertension (HTN). HTN is a major health problem in the US that affects nearly 20 percent of Americans, and constitutes one of the principal risk factors for stroke, myocardial infarction, and end-stage renal disease. HTN is a complex multifactorial disorder resulting from cumulative effects of multiple environmental and genetic factors. Despite recent progress in molecular characterization of HTN, the number and identity of underlying genes remain poorly understood. To date, the search of genetic determinants of HTN has been focused on the nuclear genome, whereas the role of the mitochondrial genome, present in multiple copies in every cell in every tissue, has not been ascertained. Given recent results of genetic studies that evidence excess maternal inheritance of HTN in Caucasians and African Americans; the age-related clinical manifestations of HTN and the importance of mitochondria in the process of aging; the identification of mitochondrial DNA (mtDNA) mutations underlying various common disorders, including diabetes and several cardiovascular diseases; we hypothesize that mitochondnal genome contributes to etiology of HTN. To test this hypothesis, we propose three specific aims. 1) We will conduct, for the first time, a systematic and extended screening of hypertensive individuals to identify potentially pathogenic mtDNA mutations. 2) Case-control association studies will be conducted to ascertain relevance of the identified mutations to HTN. 3) Functional consequences of specific mtDNA variants will be evaluated by biochemical and metabolic assays of cybrids generated with patients' mitochondria. We will employ modern, high throughput molecular genetic technologies, such as robotic workstations, ABI377 automated sequencer, and mass spectrometry, to assist in mutation identification. Use of such technology will be critical given the large number of subjects to be evaluated. Success of this project has high likelihood to provide a new dimension in HTN research, permit preclinical identification of susceptible individuals, lead to new therapies directed toward specific underlying abnormalities, and development of animal models to test them. This project is designed to interact with an ongoing Hypertension SCOR at Boston University. We will pursue a new line of inquiry into the genetics of HTN utilizing unparalleled patient resources of the present SCOR that include over 1500 blood samples and family history and clinical information from multi-generation families, sib-pairs, and isolated hypertensive cases and normotensive controls, ascertained at FITN clinics associated with Boston Medical Center; as well as expertise of uniquely qualified clinicians, epidemiologists and geneticists.